HU187086B - Process for preparing new oxazino-benzothiazine-6,6-dioxide derivatives - Google Patents

Description

The present invention relates to novel oxazinobenzothiazine-6,6-dioxide derivatives of the general formula (I) and to pharmaceutical compositions containing them as an active ingredient.

In the formula (I), R is a straight or branched C 1 -C 4 alkyl group, preferably a methyl or ethyl group,

X is oxygen or sulfur,

Seven is optionally a methyl group! substituted pyridyl, pyrimidinyl or isoxazolyl, which contains the nitrogen atom at the ortho position to its carbon atom attached to the oxazing ring.

Examples of Sev in the compounds of formula I include 2-pyridyl, 4-methyl-2-pyridyl, 6-methyl-2-pyridyl, 2-pyrimidinyl-5-methyl-3-isoxazolyl,

3-isoxazolyl and 5-isoxazolyl are mentioned.

The compounds of formula (I) are prepared according to the process of the invention by reacting a 2-alkyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3-alkyl of formula (II). - carboxylation - in the formula

R 1 and R 1 each independently represent a straight or branched C 1 -C 4 alkyl group, preferably a methyl or ethyl group, with an in situ intermediate of formula (III)

Seven is the reaction of formula (I).

The reaction may be carried out by bulking or in an inert high-boiling solvent such as diethylene glycol dimethyl ether or the like, an aromatic hydrocarbon such as methylnaphthalene or another hydrocarbon such as decalin or tetralin.

The starting materials of formula II are prepared according to the method of JG Lombardino, EH Wisenian, W, M. Mc Lamore (J. Med. Chem. 14, 1171-5 (1971)) or U.S. Patent 3,501,466. .

Preferably, the intermediate of formula (III) is prepared in situ in the reaction medium, a urethane derivative of formula (V) wherein Sev is as defined for formula (1) and R2 is phenyl, ethyl, propyl, isopropyl, by thermal decomposition of n-butyl, isobutyl or tert-butyl.

(IV) Compounds of formula I can be prepared by a Het-NH ₂ amine - wherein Het is as defined above a) Cl, -COOR ₂ with alkyl or aryl chloroformate of the formula: - wherein R ₂ is above (AR Katritizky, J. Chem. Soc. 2063 (1956)), or

b) reacting with di-tert-butyl dicarbonate (D.

S. Tárbelié, Y. Yamamoto, Β. M. Popé, Proc. Nat. Acad. Sci. USA, 69, 730 (1972)).

The oxazinobenzothiazine-6,6-dioxide derivatives of formula (I) wherein X is sulfur are prepared from the corresponding compounds of formula (I) wherein X is oxygen by substitution of the carbonyl group to the thiocarbonyl group. reacting agents, such as phosphorus pentasulide or 2,4-histo- (4-methoxyphenyl) -2,4-dithio-1,2,3,4-dithia diphosphetane.

The compounds of formula (I) are useful as active ingredients in pharmaceutical formulations for human or veterinary use because of their significant anti-inflammatory activity and very low toxicity. The present invention also provides pharmaceutical compositions containing the compounds of formula (I) as active ingredients.

The preparation of compounds of formula (I) is illustrated in more detail by the following non-limiting Examples.

Example 1

- Ethyl-3- (2-pyridyl) -2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4 (3H) -dione -6,6

- production of dioxide

4.4 g (0.015 mol) of ethyl 2-ethyl-4-hydroxy-2H

1,2-benzothiazine-1,1-dioxide-3-carboxylate and 3.5 g (0.016 mol) of 2-phenoxycarbonylamino pyridine in 40 ml. reflux in diethylene glycol dimethyl ether for 30 minutes at 161 ° C under nitrogen. The mixture was cooled to room temperature and poured into 150 ml of water. The resulting precipitate was filtered off and washed with water. Recrystallization from acetone gave 3.0 g (54%) of 5-ethyl-3- (2

pyridyl) -2H, 5H -1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4- (3H) -dione 6,6-dioxide is obtained [ compound].

Melting point: 268-270 ° C

Spectroscopic data:

IR (KBr): 1185, 1355, 1415, 1635, 1705,

1795 cm -1;

1 H NMR, δ, (DMSO-d ₆ ): 1.08 (t, 3H), 3.75 (q, 2H), 7.43 (e, 2H), 7.86 (e, 5II), δ , 4 (d, 1H)

Example 2

- Preparation of methyl 3- (2-pyridyl) -2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4 (3H) -dione 6,6-dioxide

Procedure A)

14.1 g (0.05 mol) of methyl 2-ethyl-4-hydroxy-2H

- 1,2-benzothiazine-1,1-dioxide-3-carboxylate and 11.8 g (0.055 mol) of 2-phenoxycarbonylaminopyridine in a silicone oil bath heated to 210 ° C under nitrogen atmosphere. The bulking was continued for 10 minutes while the phenol was distilled under vacuum (3225 Pa). The residue was dissolved in acetone and crystallized therefrom. 12.1 g (68%) of 5-methyl -3- (2-pyridyl) -2H, 5H-1,3-oxazino [5.6

- cis [1,2] benzothiazine-2,4 (3H) -dione-6,6-dioxide is obtained (compound of formula 2).

187,086

Melting point: 259-226 ° C;

Spectroscopic data:

IR (KBr). 1185, 1355, 1410, 1640, 1710, 1790 cm ^-1 ;

'H NMR δ (DMSO-d _e): 3.02 (s, 3H), 7.52 (e, 2H), 7.92 (e, 5H), 8.52 (d, IH).

Procedure B

2.7 g (0.01 mol) of methyl 2-methyl-4-hydroxy-2H

- 1,2-benzothiazine-1,1-dioxide-3-carboxylate and 2.1 g (0.011 mol) of 2- (tert-butoxycarbonylamino) -pyridine in 30 ml of 1-methylnaphthalene at 200 'C for 15 minutes. heated in a nitrogen atmosphere. The mixture was cooled and precipitated with petroleum ether. Recrystallized from acetone 1.9 (55%) 5-methyl-3- (2-pyridyl) -2H, 5H-1,3-oxazino- [5.6 c] [1,2] benzothiazine-2,4 (3H) di-6,6-dioxide is obtained.

Melting point: 257-259 C;

Spectroscopic data:

IR (KBr): 1185, 1355, 1410, 1640, 1710, 1790 cm ^-1 ;

1 H NMR, δ, (DMSO-d ₆ ): 3.02 (s, 3H), 7.52 (e, 2H), 7.92 (e, 5H), 8.52 (d, 1H).

Example 3

- Methyl -3- (2-pyridyl) -2H, 5H-1,3 oxazino [5,6-c] [1,2] benzothiazine-2 (3H) -ion

Preparation of 4 - on - 6,6 - dioxide

8.1 g (0.02 mol) of 2,4-bis (4-methoxyphenyl) -2,4

- dithio-1,3,2,4-dithiaphosphetane and 3.6 g (0.01 mol) of 5-methyl-3- (2-pyridyl) -2H, 5H-1,3-oxazino [5.6

- c] [1,2] Benzothiazine-2,4- (3H) -dione-6,6-dioxide in 80 ml of xylene is refluxed at 140 'C for 36 hours. The mixture was chromatographed on a column containing silica gel as the stationary phase, eluting with xylene followed by chloroform. 1.4 g (38%) of 5-methyl-3- (2-pyridyl)

2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine 2 (3H) -thion-4-one -6,6-dioxide is obtained (compound of formula 3) from the chloroform solution. . The product was recrystallized from acetone.

269-271 ° C;

Spectroscopic data:

IR (KBr): 1190, 1320, 1355, 1400, 1640, 1712 cm ^-1 ;

Ή NMR δ _(DMSO-d6): 3.05 (s, 3H), 7.54 (e, 2H), 7.92 (e, 5H), 8.48 (d, IH).

Example 4

- Methyl 3- (5-methyl-3-isoxazolyl) -2H, 5H-1,3-oxazino [5,6-ej [J, 2] benzothiazine-2,4 (3H)

Production of - di - 6,6 - dioxide

2.8 g (0.01 mol) of ethyl 2-methyl-4-hydroxy-2H

- 1,2-benzothiazine-1,1-dioxide-3-carboxylate and 2.4 g (0.011 mol) of 3-phenoxycarbonylamino-5-methylisoxazole in 40 ml of 1 ml of 1-methylnaphthalene at 200 ° C for 15 minutes. is heated under a nitrogen atmosphere. The mixture was cooled and precipitated with petroleum ether. Recrystallization from acetone gave 2.2 g (61%)

- methyl -3- (5-methyl-3-isoxazolyl) -2H, 5H-1,3

Oxazino [5,6 - c] [1,2] benzothiazine - 2,4 (3H) - dione 6 6 - dioxide (compound of formula 4) is obtained. 268-269'C;

Spectroscopic data:

IR (KBr): 1185, 1360, 1400, 1640, 1715, 1788 cm ^-1 ;

¹ H NMR δ (DMSO-d _ft): 2.5 (s, 3H), 3.08 (s, 3H), 6.44 (s, IH), 7.98 (e, 4).

Example 5

Methyl -3- (2-pyrimidinyl) -2H, 5H-1,3 cxazino [5,6-c] [1,2] benzothiazine-2,4 (3H) -dione

Production of 6,6 - dioxide

2.8 g (0.01 mol) of ethyl 2-methyl-4-hydroxy-2H

- 1,2-Benzothiazine-1,1-dioxide-3-carboxylate and 2.4 g (0.011 mol) of 2-phenoxycarbonylamino-pyrimidine in 30 ml of diethylene glycol dimethyl ether are refluxed at 161 ° C for 30 minutes under nitrogen. . The mixture was cooled to room temperature and quenched into water (100 mL). The precipitate was filtered off, washed with water, boiled under stirring with acetone and filtered again. 1.8 g (50%) of 5-methyl-3- (2-pyrimidinyl) -2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4 (3H) -dione - 6.6-dioxide (5) is obtained.

Mp 282-284 ° C;

Spectroscopic data:

IR (KBr): 1180, 1355, 1400, 1632, 1710, 1787 ^cm-1;

1 H NMR, δ, (DMSO-d ₆ ): 3.05 (s, 3H), 7.93 (e, 5H), 8.95 (d, 2H).

Example 6

- Methyl -3- (4-methyl-2-pyridyl) -2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4 (3H)

Production of - di - 6,6 - dioxide

2.7 g (0.01 mol) of methyl 2-methyl-4-hydroxy-2H

1,2 - benzothiazine - 1,1 - dioxide - 3 - carboxylate and 2.3 g (0.011 mol) of 2- (tert - butoxycarbonylimino) - 4 - methyl! - Pyridine is melted in a silicone oil bath at 160 ° C under nitrogen. Continue melting for 15 minutes. The residue was dissolved in Aceton and recrystallized from it. 2.3 g (62%) of 5-methyl-3- (4-methyl-2-pyridyl) -2H, 5H

1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4- (3H) -dione 6,6-dioxide (6) is obtained. Melting point: 259-261 ° C;

Spectroscopic data:

IR (KBr): 1195, 1360, 1415, 1640, 1720, 1795 cm ^-1 ;

'H NMR δ (DMSO-d _e): 2.42 (s, 3H), 3.1 (s, 3H);

7.4 (e, 2H), 7.98 (e, 4H), 8.4 (d, 1H).

-3187 C86

Example 7

- Meth! -3- (6-methyl-2-pyridyl) 211,511 1,3-oxazino [5,6-c] [benzothiazine-2,4 (311) -dione

- 6,6 - dioxide To a solution ^{of 5}

2.8 g (0.01 mol) of ethyl 2-methyl-4-hydroxy-2H

- 1.2 - Benzothiazine - 1,1 - dioxide - 3 - carboxylate and 2.3 g (0.011 mol) of 2- (tert - butoxycarbonylamino) - 6 - methylpyridine were heated under nitrogen in a silicone oil bath at 160 ° C. , 10 for 5 minutes. The residue was dissolved in acetone and crystallized therefrom. 1.5 g (41%) of 5-methyl-3

- (6-methyl-2-pyridyl) -2H, 5H-1,3-oxazino [5.6

- cj [1,2] benzothiazine-2,4 (3H) -dione-6,6-dioxide (7) is obtained.

Mp 248-250 ° C;

Spectroscopic data:

IR (KBr): 1190, 1360, 1410, 1640, 1715, 1790 cnf> H NMR δ _(DMSO-d6): 2.43 (s, 3Hi, 3.0 (s, 3H);

7.4 (e, 2H), 7.97 (e, 5H).

The pharmacological activity of the compounds of the present invention is described below.

A) Anti-inflammatory effect

2C

2t

V _{3 is} the foot volume measured at 3 hours after carrageenan injection and

Vj is the foot volume measured 5 hours after injection of carrageenan.

The mean inflammation index (judgments ₃ and _{5 respectively} ) is calculated from the 3-hour and 5-hour values obtained with the control group.

% Edema inhibitory effect (anti-inflammatory effect) using the following formulas! calculate;

A ₃ = --½

THE,

I ₃

It, —100

Also, its

ITJ-100

X 100,

X 100

The anti-inflammatory activity of the compounds of the invention is determined by measuring the inhibition of carrageenan-induced edema, Winter, C.A., Risley, E.A. and Nuss, G.W. Proc. Soc Exp Bioi. Med., 11, 544 (1962)].

The assay was performed on male rats weighing 90 to 110 g from the Spargue-Dawey HC / CEY rat strain. The test compounds are orally suspended in a 5% gum arabic solution and, after one hour, 0.1 ml of a 1% suspension of carrageenan in 0.9% sodium chloride solution is injected into the right soles of the animals. In each case, the test compounds are administered in a volume of 10 ml / kg. Control animals were treated with 5% gum arabic solution at 10 ml / kg.

Mercury plethysmometers are used to determine the volume of each foot immediately prior to injection of carrageenan (time 0) and then at 3 and 5 hours after injection.

The inflammatory index (1 ₃ and ₃ ) at 3 and 5 hours after carrageenan injection was determined for each animal using the following formula:

3t = Ϊ3

Va

X 100:

or

V _f x 0000, where Aj represents the anti-inflammatory effect, ie% inhibition of edema, at 3 hours after injection of carrageenan,

₅ is the anti-inflammatory effect measured at 5 hours.

The anti-inflammatory effect is proportional to the logarithm of the doses used. From the log-dose-effect curve, the dose that reduces the volume of edema to 25% can be determined. Since the maximum effect that can be achieved is a 50% reduction in edema volume, the above dose, by which the edema volume can be reduced to 25%, is taken as the EDj _C value.

Table 1 shows the test results for the compounds of formula (I).

B) Analgesic effect

The analgesic effect of the compounds of Formula I is determined by measuring the reduction of acetylcholine-induced pain, Colier, Η. O.W. et al., Br. J. Pharmac. Chemother. 32, 295 (1968).

Male mice (Swiss strain) weighing 20-25 g were used. Mice are housed in separate cages. Each animal is injected intraperitoneally with 0.2 ml / 20 g of a solution of 0.32 mg / ml acetylcholine bromide, corresponding to a dose of 3.2 mg / kg acetylcholine bromide. The number of writhing or distortion of each animal is recorded for 5 minutes. After 5 minutes, the test compounds were administered in 5% gum arabic solution. At 40 and 120 minutes after the administration of the compounds, another injection of acetylcholine was administered and the number of wrinkles and distortions again monitored for 5 minutes.

Calculate the% reduction in wrinkles and distortions using the following formulas at 40 and 120 minutes after treatment:

su

₄₀ = ^N ° ^N - ^ x 100 µMn

V _o volume at time 0, ie immediately prior to carrageenan administration, 6:

020 _n ₀ -n, N _o x 100

187 086 where N _{o is} the number of wrinkles observed prior to administration of the test compound,

N _{40 is} the number of wrinkles observed in the 40th minute after administration of the test compound and

N _{120 is} the number of wrinkles observed at 120 minutes after administration of the test compound.

The% reduction in the number of wrinkles is directly proportional to the logarithm of the dose administered. From the log-dose-effect curve, determine the dose that halves the number of original wrinkles (ED ₅₀ ).

II. Table III shows the analgesic activity of the compounds prepared in the Examples herein.

Table I: Anti-inflammatory activity of compounds of formula (I)

Compound ED _S0 (mg / kg) after 3 hours 5 hours Example 1 > 40 > 40 Example 2 2.3 2.6 Example 3 > 40 > 40 Example 4 38 39 Example 5 > 40 > 40 Example 6 > 40 > 40 Example 7 20 25 phenylbutazone 17 17

II. Table I: Analgesic effect of compounds of formula I

Compound ED _S0 (mg / kg) after 40 minutes 120 min Example 1 > 160 > 160 Example 2 1.8 1.1 Example 3 25 25 Example 4 154 154 Example 5 > 160 > 160 Example 6 > 160 > 160 Example 7 7.5 10 phenylbutazone 40 35

gauze. In practice, the determination is carried out as follows:

3.5 ml of substrate solution (0.6 mg of arachidonic acid dissolved in 10 ml of buffer) and 0.5 ml of buffer solution are added to 1.5 ml of cofactor solution containing 10 mg of enzyme [0.55 mg of hydroquinone, 0.5 ml of hemoglobin and 7.7 glutathione dissolved in 12 ml 0.2 M Tris-HCl pH 8.0) and incubated at 37 ° C for 10 minutes. The enzyme reaction was stopped by the addition of 1.5 ml of 0.2 M citric acid solution and the pGE was extracted with 2 x 5 ml of ethyl acetate. The organic phase was evaporated under a stream of nitrogen at 40 ° C and the residue was dissolved in a mixture of 2 ml of methanol and 0.5 ml of 3M 31/1 potassium hydroxide. The absorbance is measured against a blank prepared by adding 0.5 ml of buffer solution instead of the substrate solution.

The activity of the enzyme is determined after a reaction time of 10 minutes by measuring the increase in optical density.

The enzyme inhibitory activity of phenylbutazone and, for example, the compound of Example 2 is determined by treating the enzyme with the test compound for 5 minutes as follows:

0.5 ml of various concentrations of phenylbutazone Add solutions of animals or test compound to 1.5 µl of cofactor solution containing 10 mg of enzyme, pre-incubate for 5 minutes at 37 ° C and add 0.5 ml of substrate solution and the mixture was incubated for an additional 10 minutes at the above temperature.

The mixture is then treated as described and the optical density is measured. Percent inhibition is calculated as the ratio of the increase in optical density in the presence or absence of inhibitors.

Ili. The concentrations required to achieve 50% inhibition are given in Table II, for phenylbutazone and for the compound prepared in Example 2.

II. Table III .: In vitro inhibition of prostaglandin synthetase (1.14.99.1) by phenylbutazone and the compound of Example 2

Compound IC ₅₀ (mol / l) phenylbutazone 3x 10 ^-4 example 1 x 10 ^-4

C) Inhibition of prostaglandin synthetase from bovine semen

Inhibition of prostaglandin synthase by Yoshimoto et al. Biochem. 68, 487 (1970) 1.

The activity of prostaglandin synthetase (1.14,99.1) is determined by measuring the increase in absorption due to the conversion of prostaglandin E into alkaline medium B at 278 nm.

The incubation is always protected at 37 ± 0.1 ° C (d) Acute toxicity

The acute toxicity of the compounds of the present invention is described by Litchfield and Wilcoxon, J. Med. óharmacol. Exp. Therap. 96, 19 (1949)].

The compounds were orally suspended in 5% gum arabic at a volume of 25 ml / kg for mice and 10 ml / kg for rats. The LD ₅₀ values are calculated according to the above method. The acute toxicity data obtained for the compound of Example 2 are shown in Table IV. Table.

187,085

ARC. spreadsheet species gender LD ₅₀ (mg / kg) after Mouse male female 6192 8841 Rat male female 1434 1994

Because of their excellent pharmaco-dynamic properties, the oxazinobenzylazoline-6,6-dioxide derivatives of the formula (I) according to the invention are useful in both human and veterinary medicine, in particular for the treatment of acute or chronic disorders which are anti-inflammatory and / or analgesic. agents for treating arthritis associated with deformity, osteoarthritis, arthritis, skeletal muscle disorders and acute gout.

The dose used in human medicine will, of course, depend on the severity of the disorder being treated. Generally, a dose of 40-100 mg / day may be administered. The active compounds of the general formula (I) can be formulated, for example, in the form of tablets, capsules or suppositories. For example, the following pharmaceutical compositions may be prepared from the active compounds of the present invention:

Preparation of capsules

5-Methyl-3- (2-pyridyl) -2H, 5H1, 3-oxazino [5,6-c] [1,2] benzothiazine-2,4 (3H) -dione-6,6-dioxide 0.020 g

Lactose 0.136 g

Talcum 0.0016 g

Magnesium stearate 0.0016 g

Aerosil-200 0.0008 g

Capsule weight: 0.160 g

Making a tablet

5-Methyl-3- (2-pyridyl) -2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,3 (3H) -dione-6,6-dioxide 0.020 g

Avicel pH 102 0.016 g

Lactose 0.055 g

Primojel 0.003 g

Poly (vinylpyrrolidone) 0.005 g

Magnesium stearate 0/01 01 g

Tablet weight: 0.100 g

Making cones

5-Methyl-3- (2-pyridyl) -2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4 (3H) -dione-6,6-dioxide 0.050 g

Monolene 1,950 g

Cone weight: 2,000 g

Claims (7)

Patent claims A process for the preparation of a novel oxazino benzothiazine-6,6-dioxide derivative of formula (I): R is a straight or branched C 1 -C 4 alkyl group, preferably methyl or ethyl, X is oxygen or sulfur, Seven represents a pyridyl, pyrimidinyl or isoxazolyl group optionally substituted with a methyl group which contains a nitrogen atom at the ortho position to the carbon atom bound to the oxazino ring, characterized in that a compound of formula II in which R and R 1 are each independently a linear or branched C 1 -C 4 alkyl group which is reacted with an in situ intermediate of formula III wherein Sev is as defined herein and a resulting compound of formula I wherein X is O optionally, a compound of formula I wherein X is sulfur, with a source of sulfur, preferably phosphorus pentasulfide or 2,4-bis (4-methoxyphenyl) -2,4-dithio-1,2,3 , 4 - dithiophosphetane. 2. A process according to claim 1 wherein R and R are a starting material of formula (II) which is methyl or ethyl. 3. A process according to claim 1, wherein the reactant is a urethane derivative of formula (IV): wherein: Sev is as defined in the scope of claim 1 and R ₂ is an intermediate of formula (III) obtained by in situ heat generation of phenyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl. 4. A process according to claim 1 for the preparation of compounds of formula I wherein R is methyl or ethyl, wherein R is methyl or ethyl as starting material. A process according to claim 1 for the preparation of compounds of formula I wherein Sev is 2-pyridyl, 4-methyl-2-pyridyl, 6-methyl-2-pyridyl, 2-pyrimidinyl, 5-methyl-3-isoxazolyl, 3-isoxazolyl, or 5-isoxazolyl, wherein the reactant is a compound of formula (III) wherein Sev is as defined above. The method of claim 1 5-ethyl-3- (2-pyridyl) -2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4 (3H) -dione-6,6-dioxide; 5-methyl-3- (2-pyridyl) -2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4 (3H) -dione -6,6-dioxide; 187,086 5-methyl-3- (2-pyridyl) -2H, 5H -. 1,3-oxazino [5,6-c] [1,2] benzothiazin-2 (3H) -thion-4-one 6,6-dioxide; 5-methyl-3- (5-methyl-3-isoxazolyl) -1H, 5H 1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4 (3H) -dione 6,6-dioxide; 5-methyl-3- (2-pyrimidinyl) -2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4 (3H) -dione 6,6-dioxide; 5-methyl-3- (4-methyl-2-pyridyl) -2H, 5H-1,3 - oxazino [5,6-c] [1,2] benzothiazine-2,4 (3H) -dione 6,6-dioxide or « 5-methyl-3- (6-methylpyridyl) -2H, 5H-1,3 °, azino [5,6-c] [1,2] benzothiazine-2,4 (3H) -dione 6 6-dioxide preparation, wherein the baseline text / ületként use of (II) and (III) a compound of formula ^5. 7. A process for the preparation of a pharmaceutical composition, characterized in that a compound of formula (I), wherein R, X and Sev are as defined in claim ¹ θ 1, prepared according to the process of claim 1, is a carrier commonly used in pharmaceutical preparation. and / or mixed with excipients to form a pharmaceutical composition.